biostudies-literatureMartinez-Parra JMEuropean Research Council6987https://www.ebi.ac.uk/biostudies/studies/S-EPMC11325010biostudies-literatureUnknown15(1)The structure of helical polymers is dictated by the molecular chirality of their monomer units. Particularly, macromolecular helices with monomer sequence control have the potential to generate chiral topologies. In α-helical folded peptides, the sequential repetition of amino acids generates a chiral layer defined by the amino acid side chains projected outside the amide backbone. Despite being closely related to peptides' structural and functional properties, to the best of our knowledge, a general exo-helical symmetry model has not been yet described for the α-helix. Here, we perform the theoretical, computational, and spectroscopic elucidation of the α-helix principal exo-helical topologies. Non-canonical labeled amino acids are employed to spectroscopically characterize the differentNature communicationsExo-chirality of the α-helix.PMC11325010677786838002Gomez-Ojea RCalvelo MDaudey GABergueiro JMartinez-Parra JMMontenegro JFernandez-Caro HfalseExo-chirality of the α-helix.The structure of helical polymers is dictated by the molecular chirality of their monomer units. Particularly, macromolecular helices with monomer sequence control have the potential to generate chiral topologies. In α-helical folded peptides, the sequential repetition of amino acids generates a chiral layer defined by the amino acid side chains projected outside the amide backbone. Despite being closely related to peptides' structural and functional properties, to the best of our knowledge, a general exo-helical symmetry model has not been yet described for the α-helix. Here, we perform the theoretical, computational, and spectroscopic elucidation of the α-helix principal exo-helical topologies. Non-canonical labeled amino acids are employed to spectroscopically characterize the different2024-01-01T00:00:00Z2024 Aug2025-04-19T14:50:23.571Z2025-04-19T14:50:23.571ZS-EPMC113250103914305410.1038/s41467-024-51072-8